Obesity is defined as an increased mass of adipose tissue, and is associated with a higher risk of cardiovascular and metabolic disorders such as diabetes, hyperlipidemia and coronary heart disease (Reaven, G. M., Diabetologia 38, 3-13 (1995); Spiegelman, B. M. et al, Cell 87, 377-389 (1996)). Impaired glucose and lipid metabolism, a hallmark of obesity and type 2 diabetes, causes increased lipid storage in insulin target tissues such as muscle and liver, thereby leading to insulin resistance (Ruderman, N. B. et al, Am. J. Physiol. 276, E1-E18 (1999); Shulman, G. I., J. Clin. Invest. 106, 171-176 (2000)). The adipose tissue itself serves as the site of triglyceride (TG) storage and free fatty acids (FFA)/glycerol release in response to changing energy demands (Spiegelman, B. M. and Flier, J. S., Cell 87, 377-389 (1996)). Adipose tissue also participates in the regulation of various types of energy homeostasis as an important endocrine organ that secretes a number of biologically active substances called “adipokines” (Matsuzawa, Y. et al, Ann. NY Acad. Sci. 892, 146-154 (1999)) such as FFA (Shulman, G. I., J. Clin. Invest. 106, 171-176 (2000)), adipsin (White, R. T. et al, J. Biol. Chem. 267, 9210-9213 (1992)), leptin (Friedman, J. M., Nature 404, 632-634 (2000)), plasminogen activator inhibitor-1 (PAI-1) (Shimomura, I. et al, Nat. Med. 2, 800-803 (1996)), resistin (Steppan, C. M. et al, Nature 409, 307-312 (2001)) and tumor necrosis factor-α (TNF-α) (Hotamisligil, G. S., J. Intern. Med. 245, 621-625 (1999)).
Adiponectin or Acrp30 (Hu, E., Liang, P. et al, J. Biol Chem. 271, 10697-10703 (1996) and others) is an adipocyte-derived hormone with multiple biological functions. It has been reported that obesity, type 2 diabetes and coronary heart disease are associated with decreased plasma adiponectin levels, and that adiponectin may have putative anti-atherogenic properties in vitro (Ouchi, N. et al, Circulation 103, 1057-1063 (2001); Yokota, T. et al, Blood 96, 1723-1732 (2000)). Also, it has been reported that an acute increase in circulating levels of Acrp30 lowers hepatic glucose production (Berg, A. H. et al, Nat. Med. 7, 947-953 (2001); Combs, T. P. et al, J. Clin. Invest. 108, 1875-1881 (2001)). Also, it has been reported that globular Acrp30 increases fatty acid oxidation in muscle, and causes weight loss in mice (Fruebis, J. et al, Proc. Natl. Acad. Sci. USA 98, 2005-2010 (2001)). Also, it has been reported that treatment with adiponectin consisting solely of the globular domain (globular adiponectin or gAd) increases fatty acid oxidation in muscle, thereby ameliorating insulin resistance in lipoatrophic mice and obese mice, while treatment with full-length adiponectin also ameliorates though less than with gAd (Yamauchi, T. et al, Nat. Med. 7, 941-946 (2001)).
Recently it has been reported that adiponectin acutely activates AMP kinase (AMPK) in skeletal muscle, thus stimulating fatty acid oxidation and glucose uptake (Yamauchi, T. et al, Nat. Med. 8, 1288-1295 (2002)), and that adiponectin chronically activates PPARα, resulting in increased fatty acid oxidation but reduced tissue TG content in the muscles, with these effects being greater with gAd than with full-length adiponectin (Yamauchi, T. et al, J. Biol. Chem. 278, 2461-2468 (2002)). Interestingly, in the liver full-length adiponectin alone acutely activates AMPK, causing a reduction in gluconeogenesis-associated molecules and stimulating fatty-acid oxidation, and moreover full-length adiponectin alone chronically activates AMPK, stimulating fatty-acid oxidation and reducing tissue TG levels in the liver. All these changes serve to enhance insulin sensitivity in vivo (Yamauchi, T. et al, Nat. Med. 8, 1288-1295 (2002); Yamauchi, T. et al, J. Biol. Chem. 278, 2461-2468 (2002)).
These effects of adiponectin are believed to be mediated by receptors on the cell surface, but adiponectin receptors have not been identified, and it is unknown whether the adiponectin receptors in the skeletal muscle and liver differ either structurally or functionally. The inventors identified a gene encoding adiponectin receptors, and discovered from a homology search that yeast YOL002c gene is a homologue (Karpichev, I. V. et al, Journal of Biological Chemistry 277, 19609-19617 (2002)). YOL002c encodes a seven transmembrane protein that plays a key role in the metabolic pathways of lipids, such as fatty acid oxidation (Karpichev, I. V. et al, Journal of Biological Chemistry 277, 19609-19617 (2002)).